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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of leptin in the control of obesity, insulin resistance and type II diabetes has been reported, however, the regulatory mechanism of leptin in animals affected by hormones is not clearly understood. In this study, the effects of insulin, epinephrine, growth hormone or dexamethasone on the expression of leptin was examined in mouse primary adipocytes. The leptin expression was also studied in the adipose tissue of the mouse treated with insulin or growth hormone (0.3 or 0.6 units/animal). Insulin (100 nM) or dexamethasone (100 nM) stimulated leptin mRNA transcription while epinephrine (100 nM) alleviated its transcription in mouse primary adipocytes. The level of leptin protein in cultured media of adipocytes treated with insulin or dexamethasone was higher than that of the control group but growth hormone or epinephrine treatment had no effect on them. Insulin administration (0.6 units/mouse) enhanced leptin mRNA as well as leptin protein in mouse adipose tissue but growth hormone administration (0.3 or 0.6 units/mouse) had no effect on them. Leptin protein level in sera of mice injected with insulin or growth hormone was not significantly different from that of control group. These results indicate that both insulin and dexamethasone stimulate leptin gene expression and secretion of its product, whereas, growth hormone has no effect on the expression of leptin gene in mouse adipocytes.
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PMID:Regulation of leptin gene expression by insulin and growth hormone in mouse adipocytes. 1179 85

Bone turnover is assessed indirectly by measurement of biochemical markers of bone turnover. Osteocalcin, a 49-amino-acid protein is a major noncollagenous protein of bone matrix, synthesized by osteoblasts and odontoblasts. Various assays exist for assessment of osteocalcin and concentrations in the same serum or plasma sample may vary enormously. The used antibodies may recognize intact osteocalcin and/or circulating fragments of osteocalcin. We here describe and validate a new automated immunoassay system for measurement of intact osteocalcin (DPC IMMULITE assay) using monoclonal antibodies (mouse) against the C-terminus of osteocalcin (AA 44-49). For detection polyclonal antibodies (goat) directed against the N-terminus (AA 1-17) conjugated with alkaline phosphatase are used. While different laboratory assays show marked clinical discordance, we evaluated our results comparatively to an established IRMA method (Nichols). We observed a highly significant correlation between both assays (r = 0.9352, p < 0.0001, n = 286) for healthy persons and also for patient samples (osteoporosis, diabetes type 1, rheumatoid arthritis). Very low inter- and intraassay covariance as well as highly significant linearity (analytical recovery near 100%) tested by serial dilutions were demonstrated for the DPC IMMULITE intact osteocalcin assay. We conclude that the IMMULITE assay is a useful method for assessment of intact osteocalcin giving valuable results in comparison to an established non-automated assay.
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PMID:Validation of a new automated immunoassay for measurement of intact osteocalcin. 1183 73

Rodents (rat and mouse) have two types of insulin (insulin I and II; each contains a universal chain A and a different composition of each type BI chain or type BII chain). The physiological role for each isomer is not yet clarified because of the lack of an appropriate separative determination method for these isomers. Thus, in this paper, a sensitive and selective HPLC-fluorescence determination method for the isomers was developed, which includes derivatization with a fluorogenic reagent for thiols, 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate, in the presence of a reducing agent, TCEP, a nonionic surfactant, n-dodecyl beta-D-maltopyranoside, and EDTA. The resultant chain A, BI, and BII derivatives were separated on a reversed-phase column (TSK gel ODS-120T, 250 x 4.6 mm i.d.) with a mobile phase containing 5 mM phosphate buffer (pH 7.0) and were detected at 505 nm with excitation at 380 nm. The detection limits for chain A, BI, and BII derivatives were 2.2, 3.4, and 3.7 fmol on column, respectively. The method was applicable to the determination of rodent insulin in a single islet of Langerhans, and the results indicated its feasibility for the investigation of the pathophysiological roles of the isomers in diabetes in the rodent.
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PMID:Determination of insulin in a single islet of Langerhans by high-performance liquid chromatography with fluorescence detection. 1203 57

We have conducted three studies to examine the role of TNFalpha in islet destruction in female nonobese diabetic mouse (NOD) mice, a model of human autoimmune diabetes, using polyethylene glycolated (PEGylated) soluble TNF receptor type I (PEG sTNF-RI) as TNFalpha antagonist. PEG sTNF-RI (3 mg/kg, sc) was given every other day to NOD mice from age wk 8 for 12 wk (study 1), from age wk 12 for 8 wk (study 2), or from age wk 8 for 3 wk, with cyclophosphamide (6 mg/mouse) injected at wk 9 to accelerate the onset of diabetes (study 3). Diabetic incidence was reduced (control vs. PEG sTNF-RI) from 68.7% (11 of 16) to 18.3% (3 of 16) in study 1, from 84.6% (11 of 13) to 28.5% (4 of 14) in study 2, and from 66.6% (8 of 12) to 23.1% (3 of 13) in study 3, respectively. The incidence of insulitis was also reduced from 91.6% (11 of 12) to 12.5% (2 of 16) in study 1 and from 100% (7 of 7) to 16.6% (2 of 12) in study 2 by PEG sTNF-RI. PEG sTNF-RI also largely preserved islet insulin content, reduced mRNA of inducible nitric oxide synthase and IL-6 in pancreases, and lowered plasma corticosterone, glycerol, and free fatty acid levels. These results confirm a pathogenic role of TNFalpha in mediating insulitis in NOD mice and suggest the prophylactic and therapeutic potential of PEG sTNF-RI for human autoimmune diabetes.
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PMID:Polyethylene glycolated recombinant TNF receptor I improves insulitis and reduces incidence of spontaneous and cyclophosphamide-accelerated diabetes in nonobese diabetic mice. 1219 62

The embryonic pancreas is thought to develop from pluripotent endodermal cells that give rise to endocrine and exocrine cells. A key guidance mechanism for pancreatic development has previously been found to be epithelial-mesenchymal interaction. Interactions within the epithelium, however, have not been well studied. Glucagon is the earliest peptide hormone present at appreciable levels in the developing pancreatic epithelium (embryonic day [E]-9.5 in mouse). Insulin accumulation begins slightly later (E11 in mouse), followed by a rapid accumulation during the "second wave" of insulin differentiation ( approximately E15). Here we found that blocking early expression and function of glucagon, but not GLP-1, an alternate gene product of preproglucagon mRNA, prevented insulin-positive differentiation in early embryonic (E11) pancreas. These results suggest a novel concept and a key role for glucagon in the paracrine induction of differentiation of other pancreatic components in the early embryonic pancreas.
Diabetes 2002 Nov
PMID:Glucagon is required for early insulin-positive differentiation in the developing mouse pancreas. 1240 14

T cell responses toward pancreatic beta cell autoantigens arise spontaneously or on immunization in many mouse strains, yet sustained islet infiltration and progressive diabetes rarely ensues. Most mouse diabetes models overcome the innocuous coexistence of anti-islet specific T cells and endogenous islets via incompletely understood mechanisms (e.g. the spontaneous disease onset of the non-obese diabetic mouse) or depend on overwhelming numbers of peripheral islet-specific T cells. We report that insulin promoter murine CD80 (RIP-CD80) transgenic mice are extraordinarily susceptible to autoantigen-induced diabetes, while spontaneous disease is rare. Autoimmunity to the pancreatic beta cell-expressed glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) was elicited by a single injection of syngeneic fibroblastoid cell lines (FCL) loaded with the immunodominant LCMV-GP peptide, gp33. While both RIP-GP(+)and RIP-CD80(+)GP(+)mice mounted moderate CD4-independent CTL responses, only CD80(+)GP(+)mice developed severe insulitis and diabetes due to islet-infiltration of activated, gp33-specific, CD8(+)T cells. Strikingly, DNA immunization using plasmids encoding LCMV-GP or murine preproinsulin also efficiently induced Ag-specific RIP-CD80-dependent diabetes. We conclude that aberrant CD80-expression in a peripheral tissue disrupts that tissue's natural resistance to CD8 T cell-mediated autoimmune destruction. This rodent model thus represents a novel approach to identify beta cell-derived autoantigenic determinants involved in the pathogenesis of autoimmune diabetes, and may also serve as a prototype approach to uncover relevant autoantigens leading to a variety of organ-specific autoimmune disorders.
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PMID:Beta cell-specific CD80 (B7-1) expression disrupts tissue protection from autoantigen-specific CTL-mediated diabetes. 1260 8

Recent knowledge concerning the Na/Ca exchanger (NCX) in the pancreatic beta-cell is reviewed. The beta-cell expresses various NCX1 splice variants in a species specific pattern (NCX1.3 and 1.7 in the rat, NCX1.2, 1.3 and 1.7 in the mouse), in variable and different proportions. In the rat beta-cell, the exchanger displays a quite high capacity, accounts for about 70% of Ca2+ extrusion and participates to Ca2+ inflow during membrane depolarization. In the mouse, however, the contribution of the exchanger to Ca2+ extrusion is more modest, and to Ca2+ inflow less evident. The exchanger has a stoichiometry of 3 Na+ for 1 Ca2+, is electrogenic, and displays a reversal potential at -20 mV. Although being of low magnitude, the current generated by the exchanger shapes glucose-induced beta-cell electrical activity and intracellular Ca2+ oscillations. For instance, a lower Na/Ca exchange activity (and subsequent inward current) in the mouse than in the rat, explains why the mouse beta-cell displays cyclic oscillations of the membrane potential, while the rat displays a staircase increase in membrane potential without such oscillations. In addition of being of importance in cell signalling, intracellular Ca2+ may also trigger apoptosis. For instance, overexpression of the exchanger increases Ca2+-dependent and -independent beta-cell death by apoptosis, a phenomenon resulting from the depletion of ER Ca2+-stores with subsequent activation of caspase-12. Na/Ca exchange overexpression also reduces beta-cell growth. Hence, the Na/Ca exchanger is a versatile system that appears to play an important role in the function, growth and demise of the beta-cell.
Diabetes Metab 2002 Dec
PMID:Na/Ca exchange and Ca2+ homeostasis in the pancreatic beta-cell. 1268 34

The nonobese mouse model of autoimmune diabetes (NOD mouse) exhibits a strain-dependent preponderance of disease in females. Castration of male NOD mice leads to an increased incidence of diabetes, suggesting that testosterone directly modulates the expression of diabetes in the NOD mouse. However, castration also modulates hypothalamic and pituitary hormone production via removal of the negative feedback effects of testosterone. One hypothalamic hormone with immunomodulatory properties whose expression is increased by castration is GnRH. To test whether the increased incidence of diabetes in castrated male NOD mice is related to an increase in GnRH activity, we treated castrated male NOD mice with Antide, a GnRH receptor antagonist, to determine the effect on the incidence and timing of onset of diabetes. The prevalence of diabetes at 40 wk of age in male NOD mice was 50% in sham-operated mice, compared with an 83% prevalence in castrated males. Antide administration prevented the increased incidence of diabetes in the castrated male mice. Antide reduced total serum IgG levels, IL-6 cytokine expression in cultured splenocytes, and the lymphocytic infiltration of islets. GnRH administration exerted reciprocal effects, leading to earlier timing of onset of diabetes and increases in serum total IgG levels. We conclude that GnRH modulates the expression of diabetes in the NOD mouse independently of gonadal steroids.
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PMID:Modulation of diabetes with gonadotropin-releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes. 1295 92

Type 1 diabetes is an immune-mediated disease critically dependent upon the interaction between antigen-presenting cells and T cells. Clearly, both CD4+ and CD8+ T cells are required, but activated CD4+ T cells are both necessary and sufficient in causing disease. The mechanism of the Th1/Th2 immunoregulatory imbalance is unclear and needs to be further investigated. CD8+ T cells are not commonly sufficient in causing disease, but CD8 T cells are necessary in initiation (<14 weeks in the NOD mouse), but not in the later (>14 weeks) effector phase of the disease. It is still unclear whether the CD8+ T cell exerts its function as a classical effector cell or mainly as an immunomodulatory cell acting in synergy with the CD4+ T cell. The relative role of T cell effector mechanisms such as Fas/FasL, perforin/granzyme, and the TRAIL systems is unclear. Proinflammatory cytokines, reactive oxygen species, and other immune mediators seem to be involved in beta cell destruction, but much is to be learned about signaling, molecular mechanisms, and in vivo importance.
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PMID:Beta cell death and protection. 1467 38

Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic beta cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 x 10(10) i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.
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PMID:Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice. 1471 2


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